Arthritis is chronic inflammation of the joint, accompanied by pain, swelling and limitation of movement in joints and connective tissue. It afflicts more than 40 million people in the United States. The most prevalent forms of arthritis are osteoarthritis and rheumatoid arthritis, both of them being progressive, degenerative diseases leading to varying degrees of disability. The cartilage and bone of the joint undergo destruction with the progress of the disease, followed by loss of mobility, and increased suffering caused, among others, by the rubbing of bone against bone.
The therapies, available at present, include palliative treatment, based on the use of analgesic or anti-inflammatory agents, and surgical therapy, comprising a partial or total joint replacement. The total replacement is used routinely for the knee, which is the most important joint usually afflicted by the disease. This is an expensive procedure that includes patient discomfort, possible serious post-operative morbidity, and risks associated with surgery involving opening up the joint. The replacement has also a drawback of limited durability, since the implanted prostheses last about 10-15 years. An alternative approach is viscosupplementation which is an injection into the joint of a biocompatible lubricant that reduces friction and pain. The rationale for this approach has its origin in the physiology of joints, where the synovium produces a highly viscous lubricating fluid, consisting of high-molecular-weight substances, such as hyaluronan and lubricin. The highly viscous nature of the synovial fluid is important for normal joint function, since it provides a nearly frictionless interface for joint movement. A molecule of hyaluronan polysaccharide (3-5×106 daltons), consisting of monosaccharides N-acetyl glucosamine and glucuronic acid, binds many water molecules in its polyanionic structure, which is important for its mechanical properties. Several viscosupplementation products, based on hyaluronan preparations, have become available in the past few years, aiming to restore the composition of the affected synovial fluid in patients with osteoarthritis, thereby providing these patients with relief from their symptoms. Hyaluronan for these viscosupplements has been usually produced from chicken combs (Synvisc™) or synthetically (Arthrease™).
Several studies have been conducted to evaluate the efficacy of exogenous hyaluronan in the treatment of osteoarthritis, and conflicting results have been reported. In a trial of 91 patients, viscosupplementation of hyaluronan did not have a significantly better effect than placebo in the treatment of osteoarthritis [Henderson K., et al.: Ann. Rheum. Dis. 53 (1994) 529-34]. In another trial, a subgroup of patients older than 60 years with more severe symptoms did report beneficial effects from viscosupplementation therapy [Wen D. Y.: Am. Fam. Physician 62 (2000) 565-70]. A meta-analysis compiling the findings of eight different studies in a total of 971 patients indicated that hyaluronan treatment was superior to a placebo in alleviating osteoarthritis-related symptoms [George E.: Ann. Rheum. Dis. 57 (1998) 637-40]. Limitations of the beneficial effects of hyaluronan injection may result from the limited stability of hyaluronan in synovial fluid. For example, the half-life of hyaluronate in sheep joint was reported to be less than 24 hours [Fraser J. R. E., et al.: Semin. Arthritis Rheum. 22(6S) (1993) 9-17]. Hyaluronic acid is probably hydrolyzed by hyaluronidase enzymes, present in mammalian tissues. Another drawback of viscosupplements made of chicken combs is a possible allergic reaction induced in individuals allergic to avian proteins, feathers, and eggs.
The availability of an efficient viscosupplementation therapy would provide relief to patients afflicted by disorders related to degenerative joint disease with joint lubrication, and in more serious cases, it would postpone the need for surgical intervention and reduce the number of operations performed. It is therefore an object of this invention to provide a viscosupplement composition exhibiting high stability in the synovial fluid.
The polysaccharides of various species of red microalgae were found to be very stable in solution, even when exposed to a wide range of pH values and temperatures [Geresh S., et al.: Biores. Technol. 38 (1991) 195-201]. There are no commercially available enzymes—carbohydrolases—capable of cleaving red microalgal polysaccharides. The main monosaccharides are xylose, glucose and galactose [Gersesh S., et al.: Carbohyd. Res. 208 (1990) 301-5] sulfated at the position 3 or 6 of the monosaccharides glucose and galactose [Lupescu N., et al.: Carbohyd. Res. 210 (1991) 349-52]. The molecular mass of the polysaccharides of the red microalgae has been estimated to be more than 3-5 million daltons.
It is an object of this invention to provide a viscosupplement composition exhibiting high stability in the synovial fluid, containing polysaccharides from red algae.
It is further an object of this invention to provide a viscosupplement composition exhibiting in vitro resistance to hyaluronidase.
Other objects and advantages of present invention will appear as description proceeds.